Mechanisms of neurodegeneration in Alzheimer disease (AD) are imperfectly understood contributing to the lack of efficient therapeutic methods. Mutants of protein Presenilin1 (PS1) cause autosomal dominant neurodegeneration in Familial AD (FAD). Thus these mutants constitute a system where mechanisms involved in AD-like neurodegeneration can be studied. Since all AD forms share clinical and neuropathological phenotypes, data derived from FAD may also illuminate pathways involved in sporadic AD (SAD). Neurotrophins and ephrins are two classes of receptor ligands that function in neuronal survival and synaptic activity and literature shows that ephrinB (efnB) and BDNF stimulate interactions of their respective receptors with the NMDAR. Recently we reported that the ability of efnB1 and BDNF (called here Factors) to protect neurons from toxicity depends on PS1 and here present data that PS1 also regulates the Factor-stimulated complexes of their cognate receptors with the NR1 subunit of the NMDAR. We also found that these complexes play crucial roles in neuroprotection. In contrast to WT neurons, neurons expressing FAD mutants are not protected by Factors from toxicity and FAD mutants inhibit the Factor-stimulated association of their receptors with NMDAR. Surprisingly, PS1FAD mutant-expressing neurons contain increased amounts of PS1- NMDAR complexes. Furthermore, PS1FAD mutant-containing NR1 complexes (necrocomplexes) do not change in response to Factor treatment. Together, our data suggest that the structure of the PS1-NR1 association of WT neurons differs from that of FAD mutant expressing neurons. Here we will elucidate mechanisms by which PS1 FAD mutants block neuroprotective activities of brain Factors by changing the structure of the PS1-NMDAR interaction. Here we also present data that the excitotoxicity-induced neuronal death in vitro may be necroptotic. We also found that PS1 FAD mutants sensitize mouse brain neurons to MCAO (ischemia)-induced death in vivo. Since MCAO-induced neuronal death involves excitotoxicity and is mediated by necroptosis, we will ask whether ischemia-induced neuronal death in FAD mutant-expressing brains correlates with necroptosis. Necroptosis was recently found activated in postmortem brains of SAD patients. Thus, we will ask whether the necroptotic pathway is activated in human FAD brains and test if survival complexes modulate the necroptotic pathway in vivo. We also obtained data that NMDAR currents decrease in PS1FAD mutant-expressing hippocampal neurons and here we will test whether FAD mutants affect the synaptic distribution of NMDAR. Since both BDNF and efnB1 modulate NMDAR currents, we will also test if FAD mutants affect modulation of NMDAR currents by Factors. Since in WT neurons Factors induce formation of survival complexes, we will test whether these complexes mediate the Factor-dependent modulation of NMDAR currents and synaptic plasticity.